Discriminative stimulus effects of a nicotine-midazolam mixture in rats

Rats were trained to discriminate the effects of nicotine (0.4 mg/kg SC) plus midazolam (0.2 mg/kg SC) from those of saline in a two-bar operant conditioning procedure involving a tandem schedule of food reinforcement. After discrimination training, the component drugs of the mixture produced very considerable amounts of drug-appropriate responding when given separately. Mecamylamine and Ro 15-1788 only slightly attenuated the discriminative response to the mixture when given separately, but completely blocked the response when administered together. In different groups of rats trained to discriminate nicotine or midazolam separately from saline, neither drug appreciably altered the dose-response curve for the other, suggesting a minimal role for pharmacological interactions when effects of mixtures were assessed. The results suggest that the two components of a compound drug-produced stimulus can be perceived separately rather than being blended into a homogenous entity. Knowledge of the characteristics of compound drug-produced stimuli may aid interpretation of the discriminative effects of single drugs with wide spectra of action.     

Overshadowing of nicotine discrimination in rats: a model for behavioural mechanisms of drug interactions?

Overshadowing can play an important role in conditioning with compound exteroceptive stimuli. Drug discrimination experiments have been carried out to examine overshadowing when mixtures of drugs serve as compound interoceptive stimuli. Three groups of rats were trained in a two-bar operant procedure with a tandem schedule of food reinforcement (n = 8). All rats were trained to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline, but in two groups of animals midazolam (0.1 or 0.2mg/kg s.c.) was co-administered with the nicotine to generate a compound stimulus. Dose-response curves were determined with nicotine and midazolam in each group. In rats trained with nicotine alone, there was a steep dose-response curve for the discriminative stimulus effect of nicotine. The presence of the smaller dose of midazolam in the training stimulus clearly attenuated, and the larger dose prevented, the appearance of the discriminative effect of nicotine, whereas there was a concomitant increase in the discriminative response to midazolam. These results suggest that midazolam overshadowed the response to nicotine in a dose-related manner. In rats trained with nicotine alone, the same doses of midazolam had no effect on the discriminative response established to the nicotine stimulus, indicating the absence of pharmacological antagonism. The results illustrate how conditioning factors may provide a behavioural mechanism for interactions between abused drugs.     

Discrimination of agonist-antagonist mixtures: experiments with nicotine plus mecamylamine

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1-0.8mg/kg s.c.). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED(50) = 0.082mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2mg/kg of mecamylamine, the ED(50) for the discriminative effect of nicotine was lowered (ED(50) = 0.036mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4-0.8mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors.     

Reversal of overshadowing in a drug mixture discrimination in rats

Previous studies have suggested that in some circumstances, learning processes such as overshadowing may determine the effects that one drug has upon the response to another. The experiments described here examined overshadowing in rats trained to discriminate mixtures of nicotine plus midazolam in two-lever operant procedures with food reinforcement. After training for 60 sessions, midazolam (0.32 mg/kg SC) overshadowed nicotine (0.32 mg/kg SC) so that the discriminative stimulus effect of nicotine seen in control rats trained with nicotine alone was abolished (n=8–10). In the next phase of the study, the discriminative response to midazolam in one group of mixture-trained rats was devalued by means of an extinction procedure which weakened the relationship between administration of midazolam and the response that was reinforced. Dose-response determinations then showed that the devaluation procedure had indeed attenuated the response to midazolam, whereas the previously overshadowed response to nicotine was restored. Post-session injections of drugs were used to equate the pharmacological histories of the groups and the effects seen were therefore attributable to training with the drugs and not simply to repeated exposure to them. Additionally, in the control rats trained with nicotine only (with midazolam given post-session), midazolam markedly reduced response rates, whereas in the three groups of rats trained with the mixture, midazolam had little response rate-depressant effect; this observation suggests that behaviourally contingent tolerance had developed to the response rate-reducing effect of midazolam. Application of devaluation procedures in studies of the discriminative stimulus effects of single drugs with multiple effects may provide a means for manipulating the characteristics of the discriminations obtained and for identifying individual elements of the drug-produced stimulus complex.     

Antagonism of a nicotine plus midazolam discriminative cue in rats

Rats were trained to discriminate nicotine (0.4mg/kg s.c.), midazolam (0.2mg/kg s.c.) or the combination of these drugs from saline (n = 10). The rats were trained to 95% accuracy in a two-bar operant procedure with a tandem schedule of food reinforcement. Testing with the individual drugs in the mixture-trained group showed that nicotine (85% drug-appropriate responding) was a more salient component than midazolam (47%) in the compound stimulus. The rats were tested with benzodiazepine and nicotine antagonists individually and in combination (mecamylamine 0.2-1.6mg/kg s.c.; flumazenil 2.5-20mg/kg i.p.). Results for the mixture-trained animals showed that flumazenil had no effect on its own, however mecamylamine on its own produced a significant but incomplete block in doses of 0.4-1.6mg/kg. The greater salience of the nicotine component of the cue would explain the block by mecamylamine but not flumazenil. The antagonists in combination produced greater blockade than mecamylamine on its own. The selectivity of the antagonist actions on the different cue components was also demonstrated. The results suggest that in drug discrimination experiments, "false negative" results may be obtained with antagonists when a training drug produces a stimulus with more than one component.     

Antagonism of AND and AND-OR drug mixture discriminations in rats

It has been suggested that use of the AND-OR training method may be associated with an enhancement of the pharmacological specificity of discriminations based on mixture of drugs. Rats were trained to discriminate a mixture of nicotine (0.4 mg/kg s.c.) plus midazolam (0.2 mg/kg s.c.) from saline (AND-discrimination, n = 8) or to discriminate the mixture from either drug alone (AND-OR discrimination, n = 6). The studies used two-lever operant procedures with food reinforcers presented on a tandem schedule. After discriminations were acquired to 80% accuracy, the nicotine antagonist mecamylamine (0.03–1.0 mg/kg s.c.) and the benzodiazepine antagonist flumazenil (0.32–10 mg/kg i.p.) were tested on the response to the mixture of nicotine plus midazolam. The antagonist effects of either mecamylamine or flumazenil given alone were more marked in rats trained under the AND-OR procedure than in rats trained on the AND-discrimination. Similarly, the antagonist effects of mixtures of mecamylamine plus flumazenil were much more potent under the AND-OR than under the AND-discrimination procedure. The AND-OR method reduced the dose of the antagonist mixture needed to produce complete block by a factor of about 10, as compared with the AND-discrimination. These striking differences in sensitivity to antagonists support the view that AND-OR or related procedures may enhance the pharmacological specificity of complex drug discriminations.     

Influence of training paradigm on specificity of drug mixture discriminations.

Generalization to different drugs and drug mixtures has been examined in rats trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed-ratio 10 schedule of food reinforcement. There was partial generalization to nicotine and midazolam and no generalization to cocaine, caffeine, or ethanol under AND-discrimination conditions and no generalization to any of these drugs in the AND-OR discrimination. Nicotine or midazolam coadministered with the training doses of pentobarbitone and amphetamine, respectively, produced full generalization in the AND discrimination and partial generalization under AND-OR conditions. Cocaine coadministered with pentobarbitone generalized fully under both procedures, but at larger doses in the AND-OR than in the AND discrimination. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. The results consistently supported the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.     

Differences between alcohol-preferring and alcohol-nonpreferring rats in ethanol generalization.

Alcohol-preferring (P rats) and alcohol-nonpreferring rats (NP rats) were trained to discriminate intraperitoneal injections of 0.5 g/kg ethanol, or subcutaneous injections of 0.6 mg/kg nicotine from saline. P rats learned the ethanol discrimination more rapidly and made a higher percentage (88%) of their responses on the ethanol lever after ethanol and a lower percentage (7%) after saline than NP rats (78 and 15%, respectively). In substitution tests, increasing doses of ethanol produced increases in the percentage of responses on the ethanol lever with similar ED50s (0.43 and 0.44 g/kg) in P and NP rats. P rats trained to discriminate ethanol from saline made more responses on the ethanol lever after nicotine (80%) and d-amphetamine (63%) than NP rats (33 and 40%). The ethanol stimulus did not generalize to morphine in either P or NP rats. NP rats trained to discriminate ethanol from saline responded more on the ethanol lever after bupropion (77%) than P rats (49%). In rats trained to discriminate nicotine from saline, the nicotine discriminative stimulus did not generalize to ethanol in either P or NP rats, suggesting that the genetic difference in the stimulus generalization of ethanol was not symmetrical.     

Nicotine trace discrimination in rats with midazolam as a mediating stimulus

It was shown previously that effects of drugs present prior to training sessions could serve as discriminative stimuli. Further experiments have aimed to determine whether a second drug can serve as a mediating stimulus that increases the strength of stimulus control by such pre-session drug effects. Rats were trained in a two-lever discrimination procedure with food reinforcers presented on a tandem variable-interval fixed-ratio (VI-FR) schedule. Injections of nicotine (0.6 mg/kg) or saline were followed after 5 min by administration of midazolam (0.2 mg/kg) as a putative mediating stimulus. The nicotine antagonist mecamylamine (1.0 mg/kg) was administered 5 min after midazolam, to block effects of nicotine during training sessions, as in previous work on pre-session drug effects. Stimulus control was acquired slowly and to an accuracy of only 75%. Midazolam did not facilitate the acquisition or magnitude of nicotine-induced stimulus control. However, extinction tests showed that the presence of midazolam was required for expression of stimulus control by pre-session effects of the training dose of nicotine. The response to nicotine (0.075-0.6 mg/kg) was dose-related, but the dose-response relationship was not dependent upon the presence of midazolam. In a group of rats trained with nicotine and midazolam as above, but without mecamylamine, stimulus control by nicotine was not dependent upon the presence of midazolam. In all cases, overall rates of responding were very low when tests were carried out without midazolam, suggesting the presence of state-dependent learning. The results imply that under appropriate conditions the discriminative stimulus effects of one drug (nicotine) can be mediated by the action of a second substance (midazolam). This finding can be conceptualized in terms of occasion setting, with nicotine serving as the feature and midazolam as the target stimulus. Furthermore, it appears that even when rates of responding show drug-state dependence, this is not necessarily the case for discriminative stimulus effects.     

Role of training dose in discrimination of nicotine and related compounds by rats

Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. There was partial generalization to the nicotine analogues anabasine and cytisine in rats trained to discriminate either 0.2 or 0.4 mg/kg nicotine from saline. However, generalization was complete in rats trained to discriminate 0.1 mg/kg nicotine and, in a novel procedure, any one of three doses of nicotine (0.1, 0.2, or 0.4 mg/kg). There was no generalization to the muscarinic-cholinergic agonist oxotremorine (0.0025–0.04 mg/kg). Additional experiments were carried to further characterize the response of rats trained with nicotine (0.1 mg/kg). These animals failed to generalize to compounds from a range of pharmacological classes (i.e., apomorphine, cocaine, chlordiazepoxide, picrotoxin, and quipazine), but there was partial generalization to amphetamine. Mecamylamine (0.5 mg/kg) but not hexamethonium (5.0 mg/kg) blocked the discrimination of nicotine and the generalization to cytisine. Anabasine (1.0–4.0 mg/kg) did not block the response to nicotine. The results support the view that the nicotine cue is mediated mainly through central cholinergic mechanisms. The dose of nicotine used for training has a very significant influence on the characteristics of the cue and 0.1 mg/kg of nicotine may be more suitable than 0.4 mg/kg as a training dose in future work.     

Discrimination of a drug mixture in rats: role of training dose, and specificity

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.     

Discriminative stimulus properties of the nicotinic agonist cytisine

Cytisine binds with high affinity and specificity to neuronal nicotinic receptors but its physiological and behavioural effects are complex and differ from those of nicotine. The present study explores the behavioural aspects further by comparing the discriminative stimulus effects of cytisine with those of nicotine. Two groups of rats were trained to discriminate cytisine (2 mg/kg SC) or nicotine (0.2 mg/kg SC) from saline in a two-lever operant conditioning procedure with food reinforcers presented on a tandem VI FR schedule. A third group of rats was trained to discriminate cytisine (3 mg/kg SC). Rats acquired these discriminations within 50 training sessions. The stimulus effects of both cytisine and nicotine appeared within 4 min of SC injection. In generalization tests, rats trained with either cytisine or nicotine showed steep dose-response curves (generalization gradients) for their respective training drug. However, rats trained with cytisine showed full dose-related, generalization to nicotine (93%), whereas rats trained with nicotine exhibited only partial generalization to cytisine (54%). Rats trained with either cytisine or nicotine exhibited similar, partial generalization (76–77%) to (+)-amphetamine. The nicotine antagonist mecamylamine blocked the discriminative stimulus effects of both cytisine and nicotine; it was confirmed that the block of nicotine (0.2 mg/kg) was complete, whereas the block of cytisine (2 and 3 mg/kg) was incomplete in two separate experiments. Overall, the results showed that cytisine, like nicotine, can serve as a robust discriminative stimulus but, in contrast to its relatively high affinity in binding experiments, cytisine was much less potent than nicotine in the behavioural studies. Although the stimulus effects of the two drugs were very similar, there were some subtle differences such as the asymmetrical cross-generalizations between them and possible small differences in susceptibility to antagonism by mecamyl-amine. These effects were interpreted either in terms of a putative partial agonist effect of cytisine, or by assuming that nicotine produces a compound stimulus. Such a stimulus would be mediated through two or more subtypes of nicotinic receptor, and cytisine would act at some, but not all, of these receptor subtypes. Received: 17 June 1996/Final version: 6 September 1996     

Tolerance to the discriminative stimulus effects of midazolam: evidence for environmental modification and dose fading

The ability of behavioral variables to modify the development of tolerance to the discriminative stimulus effects of midazolam was evaluated. Rats were trained to discriminate 0.32mg/kg s.c. or 1.0mg/kg i.p. midazolam from no-drug, under a two-lever procedure, in daily experimental sessions consisting of multiple discrete 20-min trials: 15-min time-out, followed by 5-min under a fixed-ratio 15 schedule of food pellet delivery. Generalization testing was accomplished by administering progressively increasing doses of midazolam before each time-out period. During the chronic phases, twice daily injections of 10mg/kg midazolam or saline were given while discrimination training was either suspended or continued; generalization gradients for midazolam were determined weekly for 4 weeks. Chronic saline given when training was continued or suspended produced slight fluctuations in the midazolam minimal discriminable dose (MDD) (the first dose of midazolam in an individual generalization gradient to produce >/=90% drug-lever responding). Tolerance developed to the discriminative stimulus effects of midazolam when chronic midazolam was given while training was suspended: at Week 4, chronic midazolam produced 3-to 57-fold rightward shifts in the midazolam generalization gradient. In contrast, continued training during chronic midazolam produced no tolerance to the discriminative stimulus effects of midazolam: at Week 4 of chronic midazolam the MDD of midazolam was not different from pre-chronic and not different from either saline condition. The effects of chronic midazolam on stimulus effects and response rates were differentiated: despite tolerance to the stimulus effects of midazolam, there were no consistent changes in response rates during chronic midazolam administration.     

Drug-cue conditioning to external stimulus conditions

Rats were trained to discriminate 0.04 mg/kg fentanyl from saline in a 2-lever procedure, and to discriminate 10 mg/kg pentobarbital from saline in a maze procedure. Stimulus generalization experiments in rats trained in this double discrimination indicate that the internal cues produced by these training drugs can be conditioned to the external stimulus conditions associated with the different discrimination procedures.     

Influence of training history on ethanol discrimination in rats

The compound stimulus hypothesis of ethanol discrimination predicts that a history of training to discriminate drugs that mimic individual elements of the ethanol stimulus should attenuate stimulus control by other stimulus elements (associative blocking). Rats were trained initially to discriminate either chlordiazepoxide (5 mg / kg s.c., n = 10) or dizocilpine (0.08 mg / kg i.p., n = 10) from vehicle in two-lever procedures with food reinforcers presented on a tandem variable-interval fixed ratio schedule. Control rats received 'sham training' (vehicle injections only, n = 9). All subjects were then trained to discriminate ethanol (1.5 g / kg intragastrically (i.g.)) until discrimination accuracy reached 95%. Chlordiazepoxide (1.25-10.0 mg / kg s.c.) produced more drug-appropriate responding in rats with a previous history of training to discriminate chlordiazepoxide than in either of the other two groups, but stimulus control by dizocilpine was not attenuated. Equivalent results were obtained in rats with a previous history of training to discriminate dizocilpine. Ethanol (0.375-3.0 g / kg i.g.) produced similar dose-related increases in drug-appropriate responding in all three groups. Thus, previous discrimination training modified the characteristics of ethanol discrimination in a way that may be explained by persistence of the original discriminations. The lack of evidence for associative blocking contrasts with results of previous experiments on the discrimination of compound stimuli produced by administering drug mixtures. The findings provide limited support for the hypothesis that ethanol produces a compound stimulus that includes elements of positive modulation of gamma-aminobutyric acid (GABA(A)) receptors and of N-methyl-D-aspartate (NMDA) antagonism.     

The role of fentanyl training dose and of the alternative stimulus condition in drug generalization

Different groups of rats were trained to discriminate fentanyl (F) (0.03, 0.02, or 0.01 mg/kg) from saline or to discriminate 0.03 mg/kg fentanyl (F) from alternative stimulus conditions (saline, 0.15 mg/kg nicotine, or 0.01 mg/kg F). When percentage of responses on the drug lever and percentage of time spent responding on the drug lever were used as dependent variables, it was found that training dose and alternative stimulus condition both affected the ED₅₀ and the slope of the F generalization gradient. ED₅₀ and slope values based on group data were not significantly different from values based on individual data. Differences between the results of the first and second 2.5-min period of the extinction test were not significant. ED₅₀ and slope values were unaffected by the preceding training session, except in the group trained to discriminate 0.03 from 0.01 mg/kg F. A lever selection measure showed a significant effect of alternative stimulus condition on ED₅₀ values only.Training dose and alternative stimulus condition also affected the generalization to morphine. Under none of the conditions explored in this study did generalization occur to amphetamine or nicotine. The results are discussed in terms of the relative nature of drug generalization.     

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.     

The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats

In addition to delivering nicotine, tobacco smoke also inhibits monoamine oxidase (MAO). Although MAO inhibitors (MAOIs) can increase nicotine self-administration in rodents, the effects of MAOIs on the discriminative stimulus effect of nicotine are not known. This study examined the effects of three MAOIs (phenelzine, clorgyline and pargyline) with varying selectivity for MAOA and MAOB in the nicotine drug discrimination procedure in rats. Adult male Sprague-Dawley rats were trained to discriminate nicotine (0.3 mg/kg, subcutaneously) from saline in a standard, two-lever food-reinforced operant task. Once the discrimination was acquired, the ability of each MAOI to substitute for or alter the discriminative stimulus effect of nicotine was determined. In substitution tests, nicotine (0.03-0.3 mg/kg) produced full, dose-dependent substitution. Although the selective MAOA inhibitor clorgyline (3-56 mg/kg) and the selective MAOB inhibitor pargyline (3-56 mg/kg) did not elicit any nicotine-appropriate responding, partial substitution was obtained with the nonselective MAO inhibitor phenelzine (1-17 mg/kg). Phenelzine (10 mg/kg) also enhanced the discriminative stimulus effect of a low dose of nicotine (0.056 mg/kg) and prolonged the time course effect of the nicotine-training dose. These findings indicate that concomitant inhibition of MAOA and MAOB can enhance the discriminative stimulus effect of nicotine in rats.     

Discriminative stimulus properties of triadimefon: Comparison with methylphenidate

Two groups of rats (N=4 each) were trained to discriminate either triadimefon (40 mg/kg) or methylphenidate (4 mg/kg) from saline in a two-lever, milk-reinforced drug discrimination paradigm. Dose-response functions were determined during 5-min extinction sessions. Both agents produced a dose-related increase in the percentage of responses that occurred on the drug lever. In the substitution phase of the study, rats trained to discriminate triadimefon were tested with methylphenidate and rats trained to discriminate methylphenidate were tested with triadimefon. Triadimefon substituted completely for methylphenidate and methylphenidate substituted completely for triadimefon. These results indicate that triadimefon can function as a discriminative stimulus and that it shares discriminative stimulus properties with methylphenidate.     

The conditional stimulus effects of nicotine vary as a function of training dose

Although past research has shown that the interoceptive effects of nicotine serve as a conditional stimulus using sucrose as the unconditioned stimulus, very little is known about the importance of dose. Accordingly, rats were assigned to 0.1, 0.2, or 0.4 mg nicotine base/kg as the training dose. Sucrose (4-s access) was delivered 36 times on nicotine sessions; sucrose was withheld on intermixed saline sessions. The discrimination was acquired for all groups, as measured by more photobeam breaks in the dipper receptacle before the first sucrose delivery on nicotine sessions, compared with a similar interval on saline sessions. Thirty nicotine sessions without sucrose deliveries (extinction) decreased conditioned responding with the 0.4 mg/kg dose maintaining higher responding than the lower doses. After reestablishing discrimination performance, rats were tested with their training dose at various injection-to-placement intervals. Conditioned responding diminished with longer intervals; 0.4 mg/kg nicotine-evoked conditioned responding at longer intervals. Subsequent generalization testing with nicotine or saline at the 5-min training interval found that conditioned responding was evoked by lower test doses in the 0.1 mg/kg group than in the other groups. Combined, this research demonstrates that the nicotine conditional stimulus shows some variation with training dose.